Aging is the largest single risk factor for the development of complex genetic disease including cancer, autoimmune disease, and neurodegeneration (including age-related macular degeneration - AMD). The primary theory attempting to explain the role of aging in these diseases is focused on the macromolecular damage caused by reactive oxygen species (ROS) and the genetics of susceptibility to this damage. Complex genetic disease however can also be investigated from the perspective of epigenetics. Gene expression for many genes is epigenetically regulated as a function of age, and altered expression of these genes is potentially linked to the development and progression of disease. We hypothesize that age-related change in the expression of oxidative stress genes are the result of epigenetic changes in cytosine methylation in genomic DNA in the retinal pigment epithelium (RPE)/choroid. This type of methylation is the most common epigenetic modification of the genome. We will first measure the age-related change of the expression and cytosine methylation of a set of candidate genes in the mouse RPE/choroid which are linked to oxidative stress. The set includes Er1, Err1, Foxo3a, Nrf2, Pgc11, Prdx3, p66/Shc1, Sirt1, Sod2, Txn2, Txnrd2, and 14-3-38. Our preliminary data indicate that Prdx3, Sod2, and Txn2 may be epigenetically upregulated as a function of age. Next we will validate these results for SOD2 in the human RPE using fresh frozen and/or paraffin embedded tissue. The significance of this work is the development of a new approach to understanding the age-related risk for complex genetic disease in the retinal pigment epithelium. This approach will yield new targets for drug development and potential treatments which may enhance our current management of age-related macular degeneration (AMD). PUBLIC HEALTH RELEVANCE: This proposal outlines research on the epigenetics of age-related changes in the oxidative stress response in the mouse and human retinal pigment epithelium. The goal is to identify genes that may also be epigenetically regulated in human age-related retinal degeneration. The significance of this work is to provide a deeper understanding of how age is related to retinal degeneration, and the identification of new targets for drug development. This work will eventually lead to the development of individualized treatments for blinding eye diseases.